The four members of the Janus (JAK) family of kinases (JAK1, JAK2, JAK3 and TYK2) are involved in signal transduction of inflammatory mediators implicated in the pathogenesis of several autoimmune diseases. Small molecule inhibitors of JAK kinases have demonstrated therapeutic efficacy in clinical trials in rheumatoid arthritis (RA).This poster will focus on the design, synthesis and biological activity of a series of imidazopyridazines as potent pan-JAK inhibitors. Systematic SAR efforts addressed to improve potency and permeability of starting molecules led to the identification of an advanced lead with balanced activities against JAK1-3, good pharmacokinetics and proven efficacy in the rat adjuvant-induced arthritis (AIA) model.

Imidazopyridazine derivatives as pan-JAK inhibitors for rheumatoid arthritis

244th National Meeting (2012)

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